Project Summary/Abstract The overall goal of this proposal is to understand how a therapeutically active drug delivery system (DDS) modified by hydroxychloroquine (HCQ) will affect the pharmacokinetics and anticancer activity of oxaliplatin (OX). Specifically, this proposal will assess the sensitizing effects of our previously synthesized DDS modified by HCQ, termed Chloroquine-Altered PolySaccharide (CAPS), in the context of enhancing tumor uptake, reducing primary tumor growth, and preventing liver metastasis in pancreatic cancer (PC). The poor outcomes seen in patients diagnosed with PC can largely be attributed to the development of drug resistance. Recently, the ability of combinatorial therapies to prevent resistance has been examined, which has yielded promising results. However, combination therapies like FOLFIRINOX (FOLinic acid, Fluorouracil, IRINotecan, and OXaliplatin) suffer from increasing side effects that often require lowering the dose of drug treatments below what is required to see an optimal response from the cancer or discontinuing the therapy all together. To enhance tumor sensitivity towards chemotherapeutics and prevent resistance, chemosensitizing agents are being developed. One of the most promising agents is HCQ, which through several biological mechanisms like autophagy inhibition and CXCR4 antagonism can enhance the cancer killing ability of certain drugs. Thus creating a DDS modified by HCQ can increase the efficacy of a chemotherapeutic by sensitizing PC tumors to the therapeutic in addition to improving the pharmacokinetic profile and tumor accumulation. Because OX is one of the main sources of side effects in FOLFIRINOX therapy, OX has been selected for encapsulation with CAPS. CAPS retains the biological activity of HCQ in vitro. This preserved function translated into the ability of CAPS to reduce primary tumor growth and liver metastasis of PC in vivo more than free HCQ likely through increased tumor accumulation of HCQ via the DDS. Our hypothesis is that the combination of CAPS and OX can reduce tumor growth and metastatic spread of PC compared to the combination of HCQ and OX. Secondarily, encapsulating OX within CAPS nanoparticles (Chemo-CAPS) may further improve the anticancer activity for the combination of HCQ and OX through enhanced tumor accumulation of both drugs while reducing off-target effects. To test these hypotheses, two specific aims will be used. In Specific Aim 1, OX will be encapsulated within CAPS nanoparticles (Chemo-CAPS), and the drug release and stability of Chemo-CAPS will be determined. In Specific Aim 2, a comprehensive pharmacokinetic study of CAPS and Chemo-CAPS will evaluate tissue distribution, metabolism, excretion, blood levels, and tumor uptake of HCQ and OX in mice. Then, in an orthotopic syngeneic KPC mouse model of PC, the ability of CAPS and Chemo- CAPS to reduce primary tumor growth, inhibit liver metastasis, and mitigate side effects like neuropathy will be determined.